Reflex Testing Guidelines for Immunotherapy in Non-Small Cell Lung Cancer Jimmy Ruiz, MD Assistant Professor Thoracic Oncology Program Wake Forest Comprehensive Cancer Center
Disclosures I have no actual or potential conflicts of interest in relation to this presentation.
Objectives To provide background on the immune process and how immune checkpoints work Review key clinical trials in non-small cell lung cancer (NSCLC) that utilize PD-L1 and PD-1 inhibitors and role of PD-L1 expression Use and timing of PD-L1 testing Other potentially useful biomarkers in development for checkpoint inhibitors PD-L1 liquid biopsies
Immune System Processes Tumor Resting T Cell TCR Tumor Antigen MHC CD28 Dendritic Cell B7 Lymph Node Adapted from Pardol DM. Nature Reviews. April 2012. v12; 252-264.
Immune Check Points (PD-1/PD-L1) Tumor PD-L1 PD-1 + - Anti-PD-1 Nivolumab Pembrolizumab Anti-PD-L1 Atezolizumab Durvalumab Avelumab BMS-936559 Adapted from Pardol DM. Nature Reviews. April 2012. v12; 252-264.
Primary endpoint Overall Survival Stage IIIB/IV NSCLC, Squam Nivolumab 3mg/kg IV Q2 wks (n=135) PD 1 prior platinum doublet ECOG PS 0 1 (n=272) Secondary endpoints Overall Response Rate R 1:1 Docetaxel 75mg/m2 Q3wks (n=137) PD Progression Free Survival Safety QoL
CheckMate 017- Overall Survival
Stage IIIB/IV NSCLC, Non-Squam Pre-treatment tumor sample required for PD-L1 1 prior platinum doublet R 1:1 Nivolumab 3mg/kg IV Q2 wks (n=292) PD Prior maintenance therapy allowed Prior TKI therapy allowed for known ALK/EGFR mutation Docetaxel 75mg/m2 Q3wks (n=290) PD ECOG PS 0 1 (n=582) Secondary endpoints Primary endpoint Overall Survival Overall Response Rate Progression Free Survival Safety Efficacy by tumor PD-L1 QoL
CheckMate 057- Overall Survival Borghaei H, et al. N Engl J Med. 2015;373:1627-1639.
Nivolumab and PD-L1 In CHECKMATE 017 (Squamous), PD-L1 positivity at any cutoff was not significantly prognostic nor predictive of benefit. In CHECKMATE 057, PD-L1 positivity at 5% strongly correlated with objective response (34% vs 14% for PD-L1 negative) as well as predicted an OS benefit compared with docetaxel. In all studies a significant proportion of PD-L1 negative patients benefitted from treatment (FDA did not specify any PD-L1 threshold and does not require testing).
Key entry criteria Eligible pts with locally adv or metastatic NSCLC PD-L1 TPS> 1 ECOG PS 0-1 No brain metastasis (N=1034) R Pembrolizumab 2 mg/kg Q3wks, for 24wks (N=345) Pembrolizumab 10 mg/kg Q3wks, for 24wks (N=346) Docetaxel 75mg/m2 q3wks (N=343) Endpoints Primary - PFS, OS Secondary - ORR, DoR, Safety (both PD-L1 TPS >1% and >50%)
KEYNOTE-010: Pembro v. Docetaxel Treatment Arm Median (95% CI) Months HR (95% CI) P value Pembro 2mg/kg 14.9 0.54.0002 Pembro 10mg/kg 17.3 0.50 <.0001 Docetaxel 8.2 Herbst R, et al. Lancet. 2015.
KEYNOTE-010: Pembro v. Docetaxel Herbst R, et al. Lancet. 2015.
Pembro and PD-L1 In KEYNOTE 001, PD-L1 PS > 50% had PFS and OS that were considerably longer. Duration of response was no different between the other groups (PS <1% or 1% - 49%). KEYNOTE 010, patients with higher PS were more likely to have an objective response. Responses were still observed in 10% of those with PS 1-49%.
Grigg C, et al. J Immunother Cancer. 2016.
Case Z 54-year-old male that presented to medical attention with small bowel perforation secondary to mass in the central abdomen and mesenteric masses. He underwent surgical repair of bowel perforation. Dx: Metastatic Adenocarcinoma lung primary by IHC.
Right lower pulmonary primary and multiple enlarged mediastinal lymph nodes (right subcarinal 1.1 cm, right hilar 1.8 cm, right paratracheal 1.2 cm). Malignant right pleural effusion, metastatic involvement of multiple nodal regions (including left supraclavicular, mediastinal, mesenteric, & retroperitoneal regions), left adrenal metastasis, and small bowel mesentery with surrounding fat stranding.
Case Z Carboplatin and pemetrexed for two cycles that was poorly tolerated Complicated course with HCAP requiring admission Intractable nausea and vomiting with second course CT scan with progression Nivolumab: every 2 weeks, started April 2016
Case Z
Case Z
287 patients with previously treated advanced or metastatic NSCLC Randomized Atezolizumab to docetaxel Results: Overall survival 12.6 months vs 9.7 months; HR 0.73, p = 0.04 Median duration 14.3 months vs 7.2 months Enrollment stratified by PD-L1 expression w/ IHC assay (Ventana SP142) PD-L1 positivity was categorized according to the expressing cell type or immune cell and then scored along a gradient <1%, 1 4%, 5 49%, and 50% Tx w/ Atezolizumab favored in all but the least PD-L1 positive tumors
Atezolizumab and PD-L1 Regardless of PD-L1 expression levels and including patients with PD-L1 expression of <1% = improvement in OS vs. Docetaxel. OS was 59% greater among patients in the highest tertile of PD-L1 expression. Those with no expression still had a significant 25% improvement in OS.
Companion PD-L1 Assays in Development for PD-1/PD-L1 Inhibitors Complementary in 2 nd line Companion diagnostic Complementary in 2 nd line Grigg C, et al. J Immunother Cancer. 2016.
Overall Survival in the Intention-to-Treat Population PD-L1 tumor cell expression > 50% Reck M, et al. N Engl J Med. 2016;375:1823-1833.
Testing for PD-L1 in NSCLC? When: first line reflexive testing What to test: accessible tissue Archival Fresh KEYNOTE 001: archival tissue over 6 months led to unreliable testing *concern over deterioration of PD-L1 protein. Fresh tumor biopsies were required for PD-L1 staining by IHC KEYNOTE 010: confirmed that archival tissue can be used How often to test: Unclear
Testing for PD-L1 in NSCLC? Where to test: Primary Metastases Case series suggest a reasonable concordance between both synchronous (same time but different location) and metachronous (different time) specimen in the range of 75 90% PD-L1 expression is also affected by concurrent or prior treatments, including radiation or chemotherapy, which may have been administered after a biopsy was obtained
59-year-old female with recurrent URI. CT revealed a nodular density in LUL. Underwent LUL lobectomy with removal of 4.5 cm tumor - T2N0M0, non-small cell carcinoma with giant cell features. Negative for ALK, EGFR, ROS-1 mutations, and PD-L1 negative expression. Case X
Case X 3 months later evaluated for progressive neck pain and MRI showed a foramina stenosis at C5-6 that failed conservative management. She was taken to OR for neurosurgery for continued progressive neck pain and intraoperative found the facet complex completely replaced with soft tissue that resulted in pathologic fracture. Pathology: consistent with similar primary NSCLC with giant cell features.
PD-L1 Testing in Blood? PD-L1 detection by immunohistochemistry on tumor or immune cells is standard. PD-L1 expression is controversial in predicting which patient might benefit from therapy (low positive predictive value). Significant number of patients with PD-L1 positive tumor do not respond. PD-L1 expression is not necessary for achieving objective responses in some patients. PD-L1 is a dynamic biomarker and is currently being measured as a one-time snapshot.
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Checkpoint Immunotherapy Biomarkers Evaluation Brief Description Clinical outcome correlations PD-L1 IHC assessment (% of PD-L1 + tumor and/or immune cells Mutational Burden Multiplex IHC Immune gene signatures Next generation exome sequencing for nonsynonymous somatic mutations Assessment of a number of protein markers on tumor and immune cells and there relationship with one another Assessment of tumor gene expression profiles and its microenvironment Associated improvement in response to treatment Improved response in high mutational count Improved outcomes in those displaying interaction of PD-1 + and PD-L1 + cells. Positive associations with t- cell inflamed profile, or interferon gamma
Genomic Immuno-Biomarkers High mutational load and number of mutations per exome have been correlated with improved OS. Neoantigen load in patients correlates with tobacco carcinogenrelated mutagenesis, higher neoantigen burden, and DNA repair pathway mutations. DNA mismatch repair (MMR) gene deficiency associated with a heavy mutational burden. Mutations in enzymes involved in DNA replication and repair like POLE and POLD1.
There have been rapid and significant advances as related to tumor immunotherapy treatment in NSCLC. Improvements in clinical outcomes with emerging research discoveries. Challenges: Develop an ability to predict who will respond; fewer than 25-50% of patients have a clinical benefit while on anti-pd-1 or anti- PD-L1 therapies. Patients whose disease is PD-L1-negative by immunohistochemistry can still achieve clinical benefit with anti- PD-1 or anti-pd-l1. Liquid biopsies for CTC or other soluble factors need to be fully validated in randomized prospective clinical trials. Closing
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